Avycaz Approval and Labeling Restrictions

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On Feb 25, 2015 the combination of ceftazidime/avibactam (Avycaz) was approved by FDA for cUTI and cIAI infections in patients ‘who have limited or no alternative treatment options’.  As a QIDP drug, Avycaz received priority review.  Its label states that it is indicated for infections caused by pathogens proven or ‘suspected to be susceptible’.  Post-marketing requirements are for pediatric studies and microbiologic surveillance.  We are told that there is some concern about efficacy in patients with Clcr < 50 ml/min.

The restrictions are in place because ‘safety and efficacy data for Avycaz is limited, says FDA. As we know enough about ceftazidime, I guess this goes for the avibactam component mainly.

FDA restricts Avycaz to patients‘who have limited treatment options’ – which is no restriction at all unless you practice in a place where time has stood still and all bugs are of the MDS, not MDR variety… 

So here is my first question: Which patients are actually excluded? Just about all seriously ill patients have infections with bacteria that are not pan-susceptible and can be considered to have limited treatment options. I thought that’s why we do antibiograms. Hence, the label restriction to patients with‘limited treatment’ does not really exclude anyone.

Second question: Can somebody please explain to me how to recognize a ‘suspectedly susceptible’ pathogen?  When cultures come back showing that an E.coli from a cIAI patient is resistant to a 3rd generation CPN and behaves like an ESBL, I guess it would make sense to consider Avycaz.  But it also opens the door for ‘pre-emptive’ treatment of all patients during the time window when culture and susceptibility results are pending.  What prevents the surgical service to make Avycaz the empirical therapy for cIAI when all it takes is suspicion to justify its use ?

As we have seen, these label restrictions are so soft that they amount to….very little.  In all fairness, this wording was put in place by FDA for good reasons.  Any harsher restrictions would have achieved little but scare doctors away from using the drug at all.  And further create a disincentive for industry to invest in antibiotic development.

Assume for a moment that the label would restrict Avycaz to patients with “proven infection caused by Avycaz-susceptible ceftazidime-resistant pathogens”?  Or to “ESBL producers resistant to any and all 3rd generation cephalosporins”?  Clinician would either ignore these restrictions or just use carbapenems even more than now as imipenem, meropenem, ertapenem or doripenem do not have similarly restrictive labeling.

Hence, I was secretly hoping that Actavis would raise the price tag for Avycaz to stratospheric heights to give pharmacy cost managers the creeps and make P&T committees impose restrictions, in line with local resistance patterns and microbiologic surveillance data.

Well, Actavis did not disappoint us:  According to the Medical Letter, the daily WAC for Avycaz is $855.  By comparison, the costs of a 5-day course of generic cefepime or ceftazidime is only $82 and $60, respectively.  When these drugs were still branded, the daily cost was approx. $100.  In other words, the avibactam component comes at a steep premium of more than $750/day.

There will be rebates and the like, of course, but with this kind of price differential, market forces will do what no FDA label can do: Control and restrict Avycaz use and prevent it from becoming the ‘workhorse’ antibiotic on the surgical floors.

The FDA has shown good judgement in the way it approved Avycaz based on very limited Phase 2 data.  After a decade of intransigence this is a good example how FDA can flexibly work with industry.  But let’s not go overboard in our praise: the Avycaz approval was a relatively easy decision, given what is already known about the ceftazidime.

Here some background: An AIDAC (12/5/2014) rejected an organism-based indication (for Gram-negative infections with limited treatment options) which would have included also HABP, VABP and sepsis/bacteremia.

Ceftazidime is
approved for:

  • Lower respiratory tract infections
  • Skin and skin structure infections  
  • Urinary tract infections, both complicated and uncomplicated
  • Bacterial septicemia
  • Bone and joint infections
  • Gynecologic infections
  • Intra-abdominal infections
  • Central nervous system infections

It would have been a very bold step for FDA to either (1) override the AIDAC vote and allow an organism-driven indication as requested by Cerexa which is so different from FDA’s indication-based approval paradigm; or to (2) approve Avycaz for all the indications which ceftazidime already has in its label.

Given the very limited Phase 2 data sets from the cUTI and cIAI trials (<170 patients treated with Avycaz; <100 patients clinically evaluable) provided by Cerexa/Actavis, the dosing issues discussed at the AIDAC, and the decreased efficacy in the Clcr 30-50 mL/min group, FDA made the right decision.

P.S.  The cost for ceftolozane/tazobactam (Zerbaxa) is approx. $250-300 / day

WAC = Wholesaler Acquisition Cost


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